Localization of the gene for Wieacker-Wolff syndrome in the pericentromeric region of the X chromosome

Kloos, D U; Jakubiczka, Sibylle; Wienker, Thomas F.; Wolff, Gerhard

doi:10.1007/s004390050528

Cited by 15 publications

(10 citation statements)

References 20 publications

(13 reference statements)

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“…The family also had 12 healthy males and 22 females, suggesting that the pedigree is consistent with X-linked recessive inheritance. However, the etiology was not clear until Kloos et al mapped the genetic defect to Xp11.3 ± 11.3 in 1997 (Kloos, Jakubiczka, Wienker, Wolff, & Wieacker, 1997). ZC4H2 mutations were identified as the cause of the disease (Hirata et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

A novel de novo nonsense mutation in ZC4H2 causes Wieacker‐Wolff Syndrome

Wang

Guo

et al. 2019

Molec Gen & Gen Med

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Background Wieacker‐Wolff syndrome (WWS) is a congenital X‐linked neuromuscular disorder, which was firstly reported in 1985. Zinc finger C4H2‐type containing (ZC4H2) gene has been found to be associated with the disease pathogenesis. However, the underlying mechanism remains elusive. Methods Whole‐exome sequencing was performed to identify the mutations. Expression plasmids were constructed and cell culture and immune‐biochemical assays were used to examine the effects of the mutation. Results We reported a female patient with classical symptoms of WWS and discovered a novel nonsense heterozygous mutation (p.R67X; c.199C>T) in ZC4H2 gene in the patient but not in her parents. The mutation resulted in a 66 amino‐acid truncated ZC4H2 protein. The mutation is located in the key helix domain and it altered the subcellular locations of the mutant ZC4H2 protein. X‐chromosome inactivation (XCI) pattern analysis revealed that the XCI ratio of the proband was 22:78. Conclusion Female heterozygous carriers with nonsense mutation with a truncated ZC4H2 protein could lead to the pathogenesis of Wieacker‐Wolff syndrome and our study provides a potential new target for the disease treatment.

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Section: Discussionmentioning

confidence: 99%

A novel de novo nonsense mutation in ZC4H2 causes Wieacker‐Wolff Syndrome

Wang

Guo

et al. 2019

Molec Gen & Gen Med

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“…These included patients from five different families with syndromic forms of X-linked MR, one patient with Sutherland -Haan syndrome, 4 and one patient with WieackerWolf syndrome. 5 Table 1. A different set consisting of 180 individuals from small families with presumed MRX was obtained through the Euro-MRX Consortium.…”

Section: Patients and Controlsmentioning

confidence: 99%

X-linked mental retardation: a comprehensive molecular screen of 47 candidate genes from a 7.4 Mb interval in Xp11

et al. 2006

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About 30% of the mutations causing nonsyndromic X-linked mental retardation (MRX) are thought to be located in Xp11 and in the pericentromeric region, with a particular clustering of gene defects in a 7.4 Mb interval flanked by the genes ELK1 and ALAS2. To search for these mutations, 47 brain-expressed candidate genes located in this interval have been screened for mutations in up to 22 mental retardation (MR) families linked to this region. In total, we have identified 57 sequence variants in exons and splice sites of 27 genes. Based on these data, four novel MR genes were identified, but most of the sequence variants observed during this study have not yet been described. The purpose of this article is to present a comprehensive overview of this work and its outcome. It describes all sequence variants detected in 548 exons and their flanking sequences, including disease-causing mutations as well as possibly relevant polymorphic and silent sequence changes. We show that many of the studied genes are unlikely to play a major role in MRX. This information will help to avoid duplication of efforts in the ongoing endeavor to unravel the molecular causes of MRX.

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“…Potential candidates include Wieacker-Wolff syndrome (62,63) and Miles-Carpenter syndrome (64), both of which exhibit a combination of mental retardation and distal muscle atrophy. In addition, defects in periaxin, a protein that associates with DRP2 in peripheral nerve, cause demyelination in mice and humans (43).…”

Section: ␣-Dystrobrevin Interaction With Damage/mage-e1mentioning

confidence: 99%

DAMAGE, a Novel α-Dystrobrevin-associated MAGE Protein in Dystrophin Complexes

Albrecht

Froehner

2004

Journal of Biological Chemistry

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Mice rendered null for ␣-dystrobrevin, a component of the dystrophin complex, have muscular dystrophy, despite the fact that the sarcolemma remains relatively intact (Grady, R. M., Grange, R. W., Lau, K. S., Maimone, M. M., Nichol, M. C., Stull, J. T., and Sanes, J. R. (1999) Nat. Cell Biol. 1, 215-220) Thus, ␣-dystrobrevin may serve a signaling function that is important for the maintenance of muscle integrity. We have identified a new dystrobrevin-associated protein, DAMAGE, that may play a signaling role in brain, muscle, and peripheral nerve. In humans, DAMAGE is encoded by an intronless gene located at chromosome Xq13.1, a locus that contains genes involved in mental retardation. DAM-AGE associates directly with ␣-dystrobrevin, as shown by yeast two-hybrid, and co-immunoprecipitates with the dystrobrevin-syntrophin complex from brain. This co-immunoprecipitation is dependent on the presence of ␣-dystrobrevin but not ␤-dystrobrevin. The DAMAGE protein contains a potential nuclear localization signal, 30 12-amino acid repeats, and two MAGE homology domains. The domain structure of DAMAGE is similar to that of NRAGE, a MAGE protein that mediates p75 neurotrophin receptor signaling and neuronal apoptosis (Salehi, A. H., Roux, P. P., Kubu, C. J., Zeindler, C., Bhakar, A., Tannis, L. L., Verdi, J. M., and Barker, P. A. (2000) Neuron 27, 279 -288). DAMAGE is highly expressed in brain and is present in the cell bodies and dendrites of hippocampal and Purkinje neurons. In skeletal muscle, DAMAGE is at the postsynaptic membrane and is associated with a subset of myonuclei. DAMAGE is also expressed in peripheral nerve, where it localizes along with other members of the dystrophin complex to the perineurium and myelin. These results expand the role of dystrobrevin and the dystrophin complex in membrane signaling and disease.The dystrophin glycoprotein complex links the actin cytoskeleton to the extracellular matrix in skeletal muscle. In addition, recent studies (1-7) have shown that the dystrophin complex is critical for the localization of a variety of signaling molecules to the skeletal muscle sarcolemma. Thus, the dystrophin complex functions as both a structural link to the extracellular matrix and as a scaffold that concentrates and stabilizes functionally inter-related signaling proteins at the muscle cell membrane.Part of the signaling function of the dystrophin complex may be mediated by the dystrobrevins. The role of the dystrobrevins in signaling is not fully understood; however, targeted disruption of the ␣-dystrobrevin gene in mice results in muscle pathology without the membrane fragility characteristic of dystrophin-deficient muscular dystrophy (8). These findings suggest that ␣-dystrobrevin is important for muscle function but in a non-structural way. Dystrobrevin has no enzymatic activity of its own; therefore, the involvement of dystrobrevin in signaling pathways is dependent on its interaction with other proteins.The dystrobrevins are transcribed from two separate genes, designated ␣ and ␤, that shar...

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Localization of the gene for Wieacker-Wolff syndrome in the pericentromeric region of the X chromosome

Cited by 15 publications

References 20 publications

A novel de novo nonsense mutation in ZC4H2 causes Wieacker‐Wolff Syndrome

A novel de novo nonsense mutation in ZC4H2 causes Wieacker‐Wolff Syndrome

X-linked mental retardation: a comprehensive molecular screen of 47 candidate genes from a 7.4 Mb interval in Xp11

DAMAGE, a Novel α-Dystrobrevin-associated MAGE Protein in Dystrophin Complexes

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